Hetercyclic compounds, processes for their preparation and pharmaceutical compositions containing them

ABSTRACT

Compounds of formula (I), and salts and prodrugs thereof    &lt;IMAGE&gt;  (I)  wherein Q1 is halo substituted phenyl; naphthyl; indolyl; benzthiophenyl; benzofuranyl; benzyl; or fluorenyl; . . . is an optional covalent bond; one of X and Y is H and the other is hydroxy or C1-6alkoxy, or X and Y are together =0 or =NOR5; R1 and R2 are H; C1-6alkyl optionally substituted by hydroxy, cyano, CORc, CO2Rc, CONRcRd, or NRcRd (where Rc and Rd are H, C1-6alkyl or phenyl(C0-4alkyl) optionally substituted by C1-6alkyl, C1-6alkoxy, halo and trifluoromethyl); phenyl(C1-4alkyl) (optionally substituted by C1-6alkyl, C1-6alkoxy, halo or trifluoromethyl); CORc; CO2Rc; CONRcRd; COC1-6alkylNRcRd; CONRcCOORd; or SO2Rc; R3 is H, C1-6alkyl or C2-6alkenyl; and R4 is phenyl optionally substituted by C1-6alkyl, C2-6alkenyl, C2-6alkynyl, halo, cyano, nitro, trifluoromethyl, trimethylsilyl, ORa, SRa, SORa, NRaRb, NRaCORb, NRaCO2Rb, CO2Ra or CONRaRb, where Ra and Rb are H, C1-6alkyl, phenyl or trifluoromethyl; are tachykinin antagonists.

This invention relates to a class of heterocyclic compounds which areuseful as tachykinin receptor antagonists.

The tachykinins are a group of naturally-occurring peptides found widelydistributed throughout mammalian tissues, both within the centralnervous system and in the peripheral nervous and circulatory systems.The structures of three known mammalian tachykinins are as follows:

Substance P:Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH₂

Neurokinin A:His-Lys-Thr-Asp-Ser-Phe-Val-Gly-Leu-Met-NH₂

Neurokinin B:Asp-Met-His-Asp-Phe-Phe-Val-Gly-Leu-Met-NH₂

Substance P is believed inter alia to be involved in theneurotransmission of pain sensations [Otsuka et al, "Role of Substance Pas a Sensory Transmitter in Spinal Cord and Sympathetic Ganglia" in 1982Substance P in the Nervous System, Ciba Foundation Symposium 91, 13-34(published by Pitman) and Otsuka and Yanagisawa, "Does Substance P Actas a Pain Transmitter?" TIPS (Dec. 1987) 8 506-510], specifically in thetransmission of pain in migraine (B. E. B. Sandberg et al, J. Med Chem,(1982) 25 1009; S. L. Shepeard et al., Br. J. Pharmacol. (1993), 108,11-12) and in arthritis [Levine et al in Science (1984) 226 547-549].These peptides have also been implicated in gastrointestinal (GI)disorders and diseases of the GI tract such as inflammatory boweldisease [Mantyh et al in Neuroscience (1988) 25 (3) 817-37 and D. Regoliin "Trends in Cluster Headache" Ed. Sicuteri et al Elsevier ScientificPublishers, Amsterdam (1987) page 85)]. It is also hypothesised thatthere is a neurogenic mechanism for arthritis in which substance P mayplay a role [Kidd et al "A Neurogenic Mechanism for SymmetricalArthritis" in The Lancet, 11 November 1989 and Gronblad et al"Neuropeptides in Synovium of Patients with Rheumatoid Arthritis andOsteoarthritis" in J. Rheumatol. (1988) 15(12) 1807-10]. Therefore,substance P is believed to be involved in the inflammatory response indiseases such as rheumatoid arthritis and osteoarthritis [O'Byrne et alin Arthritis and Rheumatism (1990) 33 1023-8]. Other disease areas wheretachykinin antagonists are believed to be useful are allergic conditions[Hamelet et al Can. J. Pharmacol. Physiol. (1988) 66 1361-7],immunoregulation [Lotz et al Science (1988) 241 1218-21 and Kimball etal, J. Immunol. (1988) 141 (10) 3564-9], vasodilation, bronchospasm,reflex or neuronal control of the viscera [Mantyh et al, PNAS (1988) 853235-9] and, possibly by arresting or slowing β-amyloid-mediatedneurodegenerative changes [Yankner et al, Science (1990) 250, 279-82],in senile dementia of the Alzheimer type, Alzheimer's disease and Down'sSyndrome. Substance P may also play a role in demyelinating diseasessuch as multiple sclerosis and amyotrophic lateral sclerosis [J.Luber-Narod et. al., poster presented at C.I.N.P. XVIIIth Congress, 28thJune-2nd July, 1992].

Peptide tachykinin antagonists containing an indolyl moiety aredisclosed in European patent application no. 0 394 989.

In view of their metabolic instability, peptide derivatives are likelyto be of limited utility as therapeutic agents. It is for this reasonthat non-peptide tachykinin receptor antagonists are sought.

In essence, this invention provides a class of potent non-peptidetachykinin receptor antagonists. By virtue of their non-peptide nature,the compounds of the present invention do not suffer from theshortcomings, in terms of metabolic instability, of known peptide-basedtachykinin receptor antagonists.

The present invention provides a compound of formula (I), or a salt orprodrug thereof: ##STR2## wherein Q¹ represents a phenyl groupsubstituted by one or more halo; optionally substituted naphthyl;optionally substituted indolyl; optionally substituted benzthiophenyl;optionally substituted benzofuranyl; optionally substituted benzyl; oroptionally substituted fluorenyl;

the dotted line represents an optional covalent bond;

one of X and Y represents H and the other represents hydroxy or C₁₋₆alkoxy, or X and Y together form a group ═O or ═NOR⁵ where R⁵ is H orC₁₋₆ alkyl;

R¹ and R² each independently represent H; C₁₋₆ alkyl optionallysubstituted by hydroxy, cyano, COR^(c), CO₂ R^(c), CONR^(c) R^(d), orNR^(c) R^(d) (where R^(c) and R^(d) each independently represent H, C₁₋₆alkyl or phenyl(C₀₋₄ alkyl) optionally substituted in the phenyl ring byone or more of C₁₋₆ alkyl, C₁₋₆ alkoxy, halo and trifluoromethyl);phenyl(C₁₋₄ alkyl) (optionally substituted in the phenyl ring by one ormore of C₁₋₆ alkyl, C₁₋₆ alkoxy, halo and trifluoromethyl); COR^(c) ;CO₂ R^(c) ; CONR^(c) R^(d) ; COC₁₋₆ alkylNR^(c) R^(d) ; CONR^(c)COOR^(d) ; or SO₂ R^(c) ; where R^(c) and R^(d) are as above defined;

R³ represents H, C₁₋₆ alkyl or C₂₋₆ alkenyl; and

R⁴ represents phenyl optionally substituted by 1, 2, or 3 groupsselected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, halo, cyano,nitro, trifluoromethyl, trimethylsilyl, OR^(a), SR^(a), SOR^(a), NR^(a)R^(b), NR^(a) COR^(b), NR^(a) CO₂ R^(b), CO₂ R^(a) or CONR^(a) R^(b),where R^(a) and R^(b) independently represent H, C₁₋₆ alkyl, phenyl ortrifluoromethyl.

For the avoidance of doubt, when the covalent bond represented by thedotted line is present, the compounds of formula (I) contain an olefinicdouble bond.

As used herein, the definition of each expression, when it occurs morethan once in any structure, is intended to be independent of itsdefinition elsewhere in the same structure.

Unless otherwise stated the alkyl, alkenyl and alkynyl groups referredto with respect to any of the formulae herein may represent straight,branched or cyclic groups or combinations thereof. Thus, for example,suitable alkyl groups include methyl, ethyl, n- or iso-propyl, n-, sec-,iso- or tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl,and cycloalkylalkyl groups such as cyclopropylmethyl; suitable alkenylgroups include vinyl and allyl; and suitable alkynyl groups includepropargyl.

The term "halo" as used herein includes fluoro, chloro, bromo and iodo,especially chloro and fluoro.

Where Q¹ represents optionally substituted fluorenyl, the group islinked through the bridgehead carbon atom, that is to say, C-9 of thefluorenyl moiety.

Where Q¹ represents optionally substituted naphthyl, indolyl,benzothiophenyl, benzofuranyl, benzyl or fluorenyl, suitablesubstituents include C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, halo,cyano, nitro, trifluoromethyl, trimethylsilyl, SR^(a), SOR^(a), SO₂R^(a), OR^(a), NR^(a) R^(b), NR^(a) COR^(b), NR^(a) COOR^(b), COOR^(a)or CONR^(a) R^(b), where R^(a) and R^(b) are as above defined. One ormore substituents may be present and each may be located at anyavailable ring position, except, where Q¹ is optionally substitutedindolyl, the nitrogen atom. Where Q¹ is optionally substituted indolyl,suitable nitrogen substituents include C₁₋₆ alkyl, optionallysubstituted phenyl(C₁₋₄ alkyl), COOR^(a) or CONR^(a) R^(b), whereinR^(a) and R^(b) are as above defined.

Suitable values of the group Q¹ include 3,4-dichlorophenyl, 3-indolyl,2-naphthyl, 3-naphthyl, 9-fluorenyl, benzyl, 3-benzothiophenyl and3-benzofuranyl.

Preferably Q¹ is 3-indolyl, 3-benzothiophenyl or 3,4-dichlorophenyl,more preferably 3-indolyl.

Preferably the double bond is absent.

Suitably one of X and Y represents hydroxy or C₁₋₆ alkoxy, such asmethoxy, or X and Y together represent ═O or ═NOH. Preferably one of Xand Y represents methoxy, or X and Y together represent ═O Morepreferably X and Y together represent ═O.

Suitable values for R¹ and R² include H, C₁₋₆ alkyl, COR^(c), CO₂ R^(c),CONR^(c) R^(d) and COC₁₋₆ alkylNR^(c) R^(d), where R^(c) and R^(d) areas previously defined. Preferably R¹ and R² are selected from H, COR^(c)and COC₁₋₆ alkylNR^(c) R^(d). More preferably, one of R¹ and R²represents H and the other of R¹ and R² is selected from H, COR¹³ (whereR¹³ is C₁₋₆ alkyl, such as methyl or cyclopropyl, or phenyl(C₀₋₃ alkyl),such as phenyl or phenylpropyl),or COC₁₋₆ alkylN(C₁₋₆ alkyl)₂.Particularly preferred are compounds wherein one of R¹ and R² representsH and the other of R¹ and R² represents CO(CH₂)_(n) N(CH₃)₂ where n is 3or 4.

One subgroup of compounds according to the invention is represented bycompounds of formula (I) wherein R³ is H or C₁₋₆ alkyl.

Preferably R³ represents H or methyl, more preferably H.

Preferably R⁴ represents substituted phenyl. Suitable phenylsubstituents include nitro, trifluoromethyl, trimethylsilyl, bromo,chloro, fluoro, iodo, cyano, methyl, ethyl, cyclopropyl, t-butyl, vinyl,methoxy, phenoxy and amino. Preferably R⁴ represents disubstitutedphenyl, more preferably 3,5-disubstituted phenyl.

Particularly preferred are compounds wherein R⁴ represents3,5-bis(trifluoromethyl)phenyl.

One subgroup of compounds according to the invention is represented bycompounds of formula (Ia), and salts and prodrugs thereof: ##STR3##wherein X and Y are as defined for formula (I);

the dotted line represents an optional covalent bond;

Z represents O, S or NR¹⁴ (where R¹⁴ is H, C₁₋₆ alkyl, optionallysubstituted phenyl(C₁₋₄ alkyl), CO₂ R^(a) or CONR^(a) R^(b), where R^(a)and R^(b) are as previously defined), preferably S or NH;

R¹⁰ is H, COR^(c), CO₂ R^(c), CONR^(c) R^(d) or COC₁₋₆ alkylNR^(c) R^(d)(where R^(c) and R^(d) are as previously defined), preferably CO(C₁₋₆alkyl) or COC₁₋₆ alkylN(C₁₋₆ alkyl)₂ ;

R¹¹ and R¹² each independently represent H, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, halo, cyano, nitro, trifluoromethyl, trimethylsilyl,OR^(a), SR^(a), SOR^(a), NR^(a) R^(b), NR^(a) COR^(b), NR^(a) CO₂ R^(b),CO₂ R^(a) or CONR^(a) R^(b), where R^(a) and R^(b) are as previouslydefined;

each R¹⁵ may occupy any available carbon atom of the bicyclic ringsystem and independently represents C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, halo, cyano, nitro, trifluoromethyl, trimethylsilyl, OR^(a),SR^(a), SOR^(a), NR^(a) R^(b), NR^(a) COR^(b), NR^(a) CO₂ R^(b), CO₂R^(a) or CONR^(a) R^(b), where R^(a) and R^(b) are as previouslydefined; and

q is 0, 1, 2 or 3, preferably 0.

A further subgroup of compounds according to the invention isrepresented by compounds of formula (I) wherein Q¹ represents indolyl,benzothiophenyl or dichlorophenyl, preferably 3-indolyl,3-benzothiophenyl or 3,4-dichlorophenyl; R¹ and R² are selected from H,C₁₋₆ alkyl, COR^(c), CO₂ R^(c) and COC₁₋₆ alkylNR^(c) R^(d) ; and R⁴ is3,5-bistrifluoromethylphenyl. Preferred are compounds according to thissubgroup wherein at least one of R¹ and R² is H.

For use in medicine, the salts of the compounds of formula (I) will bepharmaceutically acceptable salts. Other salts may, however, be usefulin the preparation of the compounds according to the invention or oftheir pharmaceutically acceptable salts. Suitable pharmaceuticallyacceptable salts of the compounds of this invention include acidaddition salts which may, for example, be formed by mixing a solution ofthe compound according to the invention with a solution of apharmaceutically acceptable acid such as hydrochloric acid, sulphuricacid, oxalic acid, fumaric acid, p-toluenesulphonic acid, maleic acid,succinic acid, acetic acid, citric acid, tartaric acid, carbonic acid orphosphoric acid. Salts of amine groups may also comprise quaternaryammonium salts in which the amino nitrogen atom carries a suitableorganic group such as an alkyl, alkenyl, alkynyl or aralkyl moiety.Thus, for example, when both R¹ and R² are other than hydrogen, thenitrogen atom to which they are attached may be further substituted togive a quaternary ammonium salt. Furthermore, where the compounds of theinvention carry an acidic moiety, suitable pharmaceutically acceptablesalts thereof may include metal salts such as alkali metal salts, e.g.sodium or potassium salts; and alkaline earth metal salts, e.g. calciumor magnesium salts.

The present invention includes within its scope prodrugs of thecompounds of formula (I) above. In general, such prodrugs will befunctional derivatives of the compounds of formula (I) which are readilyconvertible in vivo into the required compound of formula (I).Conventional procedures for the selection and preparation of suitableprodrug derivatives are described, for example, in "Design of Prodrugs",ed. H. Bundgaard, Elsevier, 1985.

The compounds according to the invention may exist both as enantiomersand as diastereomers. It is to be understood that all such isomers andmixtures thereof are encompassed within the scope of the presentinvention.

The invention also provides pharmaceutical compositions comprising oneor more compounds of this invention in association with apharmaceutically acceptable carrier. Preferably these compositions arein unit dosage forms such as tablets, pills, capsules, powders,granules, solutions or suspensions, or suppositories, for oral,parenteral or rectal administration, or administration by inhalation orinsufflation.

For preparing solid compositions such as tablets, the principal activeingredient is mixed with a pharmaceutical carrier, e.g. conventionaltableting ingredients such as corn starch, lactose, sucrose, sorbitol,talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, andother pharmaceutical diluents, e.g. water, to form a solidpreformulation composition containing a homogeneous mixture of acompound of the present invention, or a non-toxic pharmaceuticallyacceptable salt thereof. When referring to these preformulationcompositions as homogeneous, it is meant that the active ingredient isdispersed evenly throughout the composition so that the composition maybe readily subdivided into equally effective unit dosage forms such astablets, pills and capsules. This solid preformulation composition isthen subdivided into unit dosage forms of the type described abovecontaining from 0.1 to about 500 mg of the active ingredient of thepresent invention. The tablets or pills of the novel composition can becoated or otherwise compounded to provide a dosage form affording theadvantage of prolonged action. For example, the tablet or pill cancomprise an inner dosage and an outer dosage component, the latter beingin the form of an envelope over the former. The two components can beseparated by an enteric layer which serves to resist disintegration inthe stomach and permits the inner component to pass intact into theduodenum or to be delayed in release. A variety of materials can be usedfor such enteric layers or coatings, such materials including a numberof polymeric acids and mixtures of polymeric acids with such materialsas shellac, cetyl alcohol and cellulose acetate.

The liquid forms in which the novel compositions of the presentinvention may be incorporated for administration orally or by injectioninclude aqueous solutions, suitably flavoured syrups, aqueous or oilsuspensions, and flavoured emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil or peanut oil, as well as elixirs andsimilar pharmaceutical vehicles. Suitable dispersing or suspendingagents for aqueous suspensions include synthetic and natural gums suchas tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose,methylcellulose, polyvinylpyrrolidone or gelatin.

Compositions for inhalation or insufflation include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solvents,or mixtures thereof, and powders. The liquid or solid compositions maycontain suitable pharmaceutically acceptable excipients as set outabove. Preferably the compositions are administered by the oral or nasalrespiratory route for local or systemic effect. Compositions inpreferably sterile pharmaceutically acceptable solvents may be nebulisedby use of inert gases. Nebulised solutions may be breathed directly fromthe nebulising device or the nebulising device may be attached to a facemask, tent or intermittent positive pressure breathing machine.Solution, suspension or powder compositions may be administered,preferably orally or nasally, from devices which deliver the formulationin an appropriate manner.

The present invention further provides a process for the preparation ofa pharmaceutical composition comprising a compound of formula (I), whichprocess comprises bringing a compound of formula (I) into associationwith a pharmaceutically acceptable carrier or excipient.

The compounds of the present invention are of value in the treatment ofa wide variety of clinical conditions which are characterised by thepresence of an excess of tachykinin, in particular substance P,activity. These may include disorders of the central nervous system suchas anxiety, depression, psychosis and schizophrenia; neurodegenerativedisorders such as dementia, including senile dementia of the Alzheimertype, Alzheimer's disease and Down's syndrome; demyelinating diseasessuch as MS and ALS and other neuropathological disorders such asperipheral neuropathy, including diabetic and chemotherapy-inducedneuropathy, and postherpetic and other neuralgias; respiratory diseases,particularly those associated with excess mucus secretion such aschronic obstrucutive airways disease, bronchopneumonia, chronicbronchitis, cystic fibrosis and asthma, and bronchospasm; inflammatorydiseases such as inflammatory bowel disease, psoriasis, fibrositis,osteoarthritis and rheumatoid arthritis; allergies such as eczema andrhinitis; hypersensitivity disorders such as poison ivy; ophthalmicdiseases such as conjunctivitis, vernal conjunctivitis, and the like;cutaneous diseases such as contact dermatitis, atropic dermatitis,urticaria, and other eczematoid dermatitis; addiction disorders such asalcoholism; stress related somatic disorders; reflex sympatheticdystrophy such as shoulder/hand syndrome; dysthymic disorders; adverseimmunological reactions such as rejection of transplanted tissues anddisorders related to immune enhancement or suppression such as systemiclupus erythematosis; gastrointestinal (GI) disorders and diseases of theGI tract such as disorders associated with the neuronal control ofviscera such as ulcerative colitis, Crohn's disease and incontinence;disorders of bladder function such as bladder detrusor hyper-reflexia;fibrosing and collagen diseases such as scleroderma and eosinophilicfascioliasis; disorders of blood flow caused by vasodilation andvasospastic diseases such as angina, migraine and Reynaud's disease; andpain or nociception, for example, that attributable to or associatedwith any of the foregoing conditions, especially the transmission ofpain in migraine. The compounds of formula (I) are particularly usefulin the treatment of pain or nociception and/or inflammation anddisorders associated therewith such as, for example, neuropathy, such asdiabetic and chemotherapy-induced neuropathy, postherpetic and otherneuralgias, asthma, osteroarthritis, rheumatoid arthritis and especiallymigraine.

The present invention further provides a compound of formula (I), or asalt or prodrug thereof, for use in therapy.

The present invention further provides a compound of formula (I) or asalt or prodrug thereof for use in the manufacture of a medicament forthe treatment of physiological disorders associated with an excess oftachykinins, especially substance P.

The present invention also provides a method for the the treatment orprevention of physiological disorders associated with an excess oftachykinins, especially substance P, which method comprisesadministration to a patient in need thereof of a tachykinin reducingamount of a compound or composition of this invention.

In the treatment of conditions involving actions of tachykinins releasedphysiologically in response to noxious or other stimuli, a suitabledosage level is about 0.001 to 50 mg/kg per day, preferably about 0.005to 10 mg/kg per day, and especially about 0.005 to 5 mg/kg per day. Thecompounds may be administered on a regimen of 1 to 4 times per day,preferably once or twice daily.

Compounds of formula (I) wherein X and Y together represent ═O and thedouble bond is present may be prepared by reaction of an aldehyde offormula R⁴ CHO, wherein R⁴ is as defined for formula (I) above, with acompound of formula (II): ##STR4## wherein Q¹, R¹, R² and R³ are asdefined for formula (I) and R²⁰ represents a group PR^(x) ₃ orPO(OR^(x))₂, wherein R^(x) represents phenyl or C₁₋₁₀ alkyl, in thepresence of a base.

Suitable bases include alkali metal hydrides, such as, for example,sodium hydride, and strong organic bases such as, for example,1,8-diazabicylo[5.4.0]undec-7-ene in the presence of anhydrous lithiumchloride. Preferred bases include alkali metal carbonates such aspotassium carbonate.

The reaction is conveniently effected in a suitable organic solvent,such as an ether, e.g. tetrahydrofuran, suitably at ambient temperature.

The compounds of formula (I) so prepared may be converted to othercompounds of formula (I) using standard procedures, as follows. It is tobe understood that any suitable combination of the conversion processesdescribed may be employed in order to arrive at the desired compound offormula (I).

Compounds of formula (I) wherein one of X and Y represents H and theother represents hydroxy may be prepared from the correspondingcompounds of formula (I) wherein X and Y together represent ═O, byreduction.

Suitable reducing agents include, for example, hydride reducing agentssuch as lithium aluminium hydride and sodium borohydride.

The reaction is conveniently carried out in a suitable organic solvent,such as an ether, e.g. tetrahydrofuran, suitably at ambient temperature.

Compounds of formula (I) wherein one of X and Y represents H and theother represents C₁₋₆ alkoxy may be prepared from the correspondingcompounds of formula (I) wherein one of X and Y represents H and theother represents hydroxy, by alkylation.

Suitable alkylation procedures include treatment of an alcohol offormula (I) with an alkali metal hydride, such as sodium hydride, and aC₁₋₆ alkylhalide. Suitable halides include, in particular, bromides andiodides.

The reaction is conveniently effected in an anhydrous organic solvent,for example, an ether, e.g. dimethoxyethane, suitably at ambienttemperature.

Compounds of formula (I) wherein X and Y together represent ═NOR⁵ may beprepared from the corresponding compounds of formula (I) wherein X and Ytogether represent ═O by the addition of hydroxylamine, or a suitablederivative thereof. Compounds wherein R⁵ is other than H may be preparedfrom the corresponding compounds wherein R⁵ is H by alkylation, forexample, using a diazo compound, such as diazomethane, or an alkylhalide or sulphate.

Compounds of formula (I) wherein the double bond is absent may beprepared from the corresponding unsaturated compounds of formula (I) byreduction.

Suitable reduction procedures include catalytic hydrogenation. Suitablehydrogenation catalysts include nobel metals, for example, platinum orpalladium, or oxides thereof, which may be supported, for example, oncharcoal. A preferred catalyst is Wilkinson's catalyst(tris(triphenylphosphine)rhodium(I)chloride).

The reaction is conveniently effected in a suitable organic solvent,such as an ether, e.g. tetrahydrofuran, an alcohol, e.g. ethanol, or anester, e.g. ethyl acetate, suitably at ambient temperature.

Compounds of formula (I) may also be prepared from different compoundsof formula (I) via other suitable interconversion processes.Interconversion processes are particularly suitable for varying thesubstituents R¹ and R². For example, compounds of formula (I), whereinone or both of R¹ and R² is/are other than H may be prepared fromcompounds of formula (I) wherein one or both of R¹ and R² is/are H usingconventional methods, such as for example alkylation or acylation.Suitable procedures will be readily apparent to those skilled in the artand are described in the accompanying examples.

Compounds of formula (II) may be prepared from compounds of formula(III) ##STR5## wherein Q¹, R¹, R² and R³ are as defined for formula (I)and R²¹ represents an alkoxy or a suitably substituted amino group, suchas a group NR^(y) OR^(z), where R^(y) and R^(z) represent alkyl, inparticular a group NCH₃ (OCH₃), by reaction with a compound of formulaCH₃ PO(OR^(x))₂, where R^(x) is an alkyl group, in the presence of abase.

Suitable reaction procedures will be readily apparent to the skilledperson and examples thereof are described in the accompanying Examples.

Suitable bases of use in the reaction include alkyl lithiums, such asbutyl lithiums.

Compounds of formula (III) are commercially available or may be preparedusing standard procedures well known to the skilled person in the art.The compounds of formula (III) are amino acid derivatives. Syntheses ofamino acids and derivatives thereof are well documented and aredescribed, for example, in Chemistry and Biochemistry of the AminoAcids, ed. G. C. Barrett, Chapman and Hall, 1985.

Where the above-described processes for the preparation of the compoundsaccording to the invention give rise to mixtures of stereoisomers, theseisomers may be separated, suitably by conventional techniques such aspreparative chromatography.

The novel compounds may be prepared in racemic form, or individualenantiomers may be prepared either by enantiospecific synthesis or byresolution. The novel compounds may, for example, be resolved into theircomponent enantiomers by standard techniques, such as the formation ofdiastereomeric pairs by salt formation with an optically active acid,such as (-)-di-p-toluoyl-d-tartaric acid and/or(+)-di-p-toluoyl-l-tartaric acid followed by fractional crystallizationand regeneration of the free base. The novel compounds may also beresolved by formation of diastereomeric esters or amides, followed bychromatographic separation and removal of the chiral auxiliary.

During any of the above synthetic sequences it may be necessary and/ordesirable to protect sensitive or reactive groups on any of themolecules concerned. This may be achieved by means of conventionalprotecting groups, such as those described in Protective Groups inOrganic Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973; and T. W.Greene and P. G. M. Wutts, Protective Groups in Organic Synthesis, JohnWiley & Sons, 1991. The protecting groups may be removed at a convenientsubsequent stage using methods known from the art.

The following non-limiting Examples illustrate the preparation ofcompounds according to the invention.

EXAMPLE 12-Acetamido-1-(3-benzo[b]thienyl)-5-(3,5-bistrifluoromethylphenyl)-4-penten-3-onea) 2-Acetamido-1-(3-benzo[b]thienyl)-4-diethylphosphono-3-butanone

Diethyl methyl phosphonate (13.0 g) was dissolved in dry tetrahydrofuran(200 ml), cooled to -70° C., and treated with 1.6M n-butyl lithium (54ml), maintaining the internal temperature at below -60° C. The reactionmixture was stirred at -70° C. for 0.5 hours before addingN-acetyl-4-(3-benzo[b]thienyl)-DL-alanine ethyl ester (Int. J. peptideProtein Res., 29, 1987, 118-125) (10.0 g) in dry tetrahydrofuran (100ml). After stirring for 1.5 hours the reaction was quenched withsaturated ammonium chloride. The reaction mixture was extracted withethyl acetate and washed with water (3×50 ml). The organic phase wasdried (MgSO₄), filtered and evaporated to yield an oil which waspurified on silica using dichloromethane/methanol (95:5) to give theproduct as an oil (10.6 g).

b)2-Acetamido-1-(3-benzo[b]thienyl)-5-(3,5-bistrifluoromethylphenyl)-4-penten-3-one

A solution of the product of step (a) (10.6 g) in dry tetrahydrofuran(200 ml) was cooled to 0° C., treated with 60% sodium hydride in oil(1.07 g) and stirred for 1 hour. 3,5-Bistrifluoromethyl benzaldehyde(6.5 g) in dry tetrahydrofuran (50 ml) was added dropwise to thereaction mixture which was stirred for 1 hour before quenching withsaturated ammonium chloride. The organic layer was separated and theaqueous layer was extracted with ethyl acetate (2×100 ml). The combinedorganic extracts were washed with water (100 ml), dried (MgSO₄),filtered and evaporated. The residue was purified by chromatography onsilica using ethyl acetate/petroleum ether (bp 60-80) (2:3) to yield thetitle compound as a pale yellow solid (10.3 g), mp=172°-173° C.; found:C, 56.15; H, 3:54; N, 2.79; C₂₃ H₁₇ F₆ NO₂ S.0.25H₂ O requires C, 56.38;H, 3.60; N, 2.86%.

EXAMPLE 2 2-Acetamido-1-(3-benzo[b]thienyl)-5-(3,5-bistrifluoromethylphenyl)-4-penten-3-ol

A solution of the product of Example 1 (2.0 g) was dissolved inethanol/dichloromethane (5:1, 100 ml) and treated with sodiumborohydride (0.156 g). The reaction was stirred for 1 hour and thenpoured into water (500 ml), extracted with ethyl acetate, dried (MgSO₄),filtered, and evaporated to yield an oil which was purified bychromatography on silica using ethyl acetate/petroleum ether (bp 60°-80°C.) to yield the title compound isomer A as a pale yellow solid (0.25 g)mp=190°-191° C.; found: C, 56.19; H, 3.93; N, 2.91; C₂₃ H₁₉ F₆ NO₂S.0.25H₂ O requires C, 56.15; H, 4.00; N, 2.85%.

Further elution yielded the title compound isomer B as a pale yellowsolid (0.5 g) mp 94°-95° C., found: C, 56.24; H, 4.01; N, 2.73; C₂₃ H₁₉F₆ NO₂ S.0.25H₂ O requires C, 56.15; H, 4.00; N, 2.85%.

EXAMPLE 32-Acetamido-1-(3-benzo[b]thienyl)-5-(3,5-bistrifluoromethylphenyl)-3-methoxy-4-pentene

A mixture of the two isomeric alcohols of Example 2 (1.8 g) wasdissolved in dry dimethoxyethane (25 ml) and treated with sodium hydrideand stirred for 10 minutes before adding iodomethane (0.2 ml). Thereaction was stirred for a further 0.5 hours and then quenched withsaturated ammonium chloride and extracted with ethyl acetate. Theseparated organic layer was dried (MgSO₄), filtered, and evaporated toyield an oil which was purified by silica chromatography using ethylacetate/petroleum ether (bp 60°-80° C.), (1:1) to yield the titlecompound isomer A as a white solid (0.098 g) mp=125°-126° C.; found: C,57.21; H, 4.33; N, 2.75; C₂₄ H₂₁ F₆ NO₂ S requires C, 57.48; H, 4.22; N,2.79%.

Further elution yielded the title compound isomer B as a white solid(0.215 g), mp=164°-165° C.; found: C, 57.10; H, 4.29; N, 2.76; C₂₄ H₂₁F₆ NO₂ S requires C, 57.48; H, 4.22; N, 2.79%.

EXAMPLE 42-Acetamido-1-(3-benzo[b]thienyl)-5-(3,5-bistrifluoromethylphenyl)-3-pentanone

2-Acetamido-1-(3-benzo[b]thienyl)-5-(3,5-bistrifluoromethylphenyl)-4-penten-3-one(2.0 g) was hydrogenated in tetrahydrofuran (100 ml) using 10% Pd/C (0.5g) at 50 p.s.i. The product was purified by chromatography on silicausing ethyl acetate/petroleum ether (bp 60°-80° C.)(1:1) to yield thetitle compound as a white solid (1.2 g), mp=83°-84° C.; found: C, 56.41;H, 3.81; N, 2.84; C₂₃ H₁₉ F₆ NO₂ S requires C, 56.67; H, 3.93; N, 2.87%.

EXAMPLE 52-Acetamido-1-(3-benzo[b]thienyl)-5-(3,5-bistrifluoromethylphenyl)-3-pentanol

The compound of Example 4 (1.1 g) was treated with sodium borohydride(100 mg) in the same manner as Example 2 to yield the title compoundisomer A as a white solid (0.23 g), mp=70°-71° C.; found: C, 56.43; H,4.22; N, 2.77; C₂₃ H₂₁ F₆ NO₂ S requires C, 56.44; H, 4.32; N, 2.86%.

Further elution yielded the title compound isomer B, (0.42 g),mp=113°-114° C.; found: C, 56.27; H, 4.33; N, 2.81; C₂₃ H₂₁ F₆ NO₂ Srequires C, 56.44; H, 4.32; N, 2.86%.

EXAMPLE 6

2-Acetamido-1-(3-benzo[b]thienyl)-5-(3,5-bistrifluoromethylphenyl)-3-methoxypentane

A mixture of the two isomeric alcohols of Example 5 (1.3 g) was treatedin the same manner as Example 3 to yield the title compound isomer A,0.083 g, mp=120°-121° C.; found: C, 56.86; H, 4.27; N, 2.68; C₂₄ H₂₃ F₆NO₂ S requires C, 56.74; H, 4.66; N, 2.76%.

Further elution yielded the title compound isomer B as a white solid(0.075 g), mp=164°-166° C.; found: C, 56.67; H, 4.69; N, 2.81; C₂₄ H₂₃F₆ NO₂ S requires C, 56.74; H, 4.66; N, 2.78%.

EXAMPLE 72-Acetamido-5-(3,5-bistrifluoromethylphenyl)-1-(3-indolyl)-4-penten-3-onea) Methyl2-t-butyloxycarbonylamino-3-(3-(1-t-butyloxycarbonyl)indolyl)propionate

L-Tryptophan methyl ester hydrochloride (10 g), was suspended indichloromethane (200 ml) and triethylamine (3.98 g) was added, followedby di-t-butyl dicarbonate (8.6 g). The reaction was stirred for 1 hourbefore adding 4-dimethyl aminopyridine (4.8 g) and di-t-butyldicarbonate (21.4 g). The reaction was stirred for 16 hours and thenwashed with 10% citric acid (200 ml), water (200 ml), saturated sodiumbicarbonate solution (200 ml), water (200 ml) and dried (MgSO₄),filtered and evaporated. The residue was purified by chromatography onsilica using ethyl acetate/petroleum ether (bp 60°-80° C.) (1:4) toyield the title compound (13.2 g).

b)2-t-Butyloxycarbonylamino-5-(3,5-bistrifluoromethylphenyl)-1-(3-(1-t-butyloxycarbonyl)indolyl)-4-penten-3-one

The title compound was obtained by reaction of the product of part (a)by the method of Example 1.

c)2-Acetamido-5-(3,5-bistrifluoromethylphenyl)-1-(3-indolyl)-4-penten-3-one

The product of part (b) (1.0 g) was dissolved in methanolic hydrogenchloride and stirred for 16 hours. The solvent was removed and theresidue was dissolved in pyridine (5 ml) and acetic anhydride (1 ml) wasadded. The reaction was stirred for 16 hours and then poured ontoice/water. The mixture was extracted with ethyl acetate (2×100 ml) andthe organic extract was washed with 10% citric acid (100 ml), brine (100ml), saturated sodium bicarbonate (100 ml), dried (MgSO₄) filtered andevaporated. The residue was purified by column chromatography on silicausing isopropanol/petroleum ether (bp 60°-80° C.), (1:9), to yield thetitle compound as a pale yellow solid (0.35 g), mp=68°-70° C.; found: C,58.23; H, 4.06; N, 5.55; C₂₃ H₁₈ F₆ N₂ O₂.0.25H₂ O requires C, 58.42; H,3.94; N, 5.92%.

EXAMPLE 82-Acetamido-5-(3,5-bistrifluoromethylphenyl)-1-(3-indolyl)-3-pentanone

2-Acetamido-5-(3,5-bistrifluoromethylphenyl)-1-(3-indolyl)-4-penten-3-one(0.2 g) was treated in the same manner as Example 4 to yield the titlecompound as a white solid (190 mg), mp=50°-53° C.; found: C, 58.69; H,4.27; N, 5.78; C₂₃ H₂₀ F₆ N₂ O₂ requires C, 58.73; H, 4.29; N, 5.96%.

EXAMPLE 9 ##STR6##1-(3-Benzo[b]thienyl)-5-(3,5-bistrifluoromethylphenyl)-2-(N,N-dimethylglycinamido)-3-pentanone(a) 3-(3-Benzo[b]thienyl)-2-t-butyloxycarbonylaminopropionic acid

2-Amino-3-(3-benzo[b]thienyl)propionic acid (Int. J. Peptide ProteinRes., (1987), 29, 118) (22.9 g) and sodium carbonate (27.6 g) were addedto a mixture of water (350 ml) and 1,4-dioxane (150 ml).Di-t-butyldicarbonate (34.1 g) was added to the mixture and the reactionwas stirred for 16 hours and washed with ether (500 ml). The reactionmixture was acidified to pH 3 with solid citric acid and extracted withethyl acetate to yield the title compound (31.5 g).

(b) Methyl 3-(3-benzo[b]thienyl)-2-t-butyloxycarbonylaminopropionate

The product of Example 9(a) (31.5 g) and Cesium carbonate (15.93 g) weredissolved in methanol and the solvent was removed by evaporation. Theresidue was dissolved in dimethylformamide and iodomethane (27.8 g) wasadded. The reaction was stirred for 16 hours then the solvent wasremoved and the residue partitioned between ethyl acetate and water. Theorganic extract was washed with sodium bicarbonate solution and water,dried (MgSO₄), and evaporated. The residue was purified by columnchromatography on silica using ethyl acetate/petroleum ether (1:4) toyield the title compound (27.3 g).

(c)1-(3-Benzo[b]thienyl)-5-(3,5-bistrifluoromethylphenyl)-2-(t-butyloxycarbonylamino)-3-pentanone

Prepared from the product of Example 9(b) using the methods of Examples1 and 4.

(d)2-Amino-1-(3-benzo[b]thienyl)-5-(3,5-bistrifluoromethylphenyl)-3-pentanonehydrochloride

The product of Example 9(c) was dissolved in methanolic hydrogenchloride and stirred for 16 hours. The solvent was removed under reducedpressure to give the title compound as a white solid.

(e)1-(3-Benzo[b]thienyl)-5-(3,5-bistrifluoromethylphenyl)-2-(N,N-dimethylglycinamido)-3-pentanoneHydrochloride

N,N-Dimethyl glycine (0.206 g) and triethylamine (0.5 g) were dissolvedin dry dimethylformamide and cooled to -30° C. before addingisobutylchloroformate (0.27 g). The reaction was stirred for 20 minutesbefore adding the product of Example 9(d). The reaction was stirred for1 hour, poured into water and then partitioned between ethyl acetate andwater. The organic phase was washed with water (100 ml), sodiumbicarbonate solution (100 ml) and water. The organic extract was dried(MgSO₄), filtered and evaporated. The residue was purified by columnchromatography on silica using ethyl acetate. The resulting oil wastreated with ethereal hydrogen chloride and the solid produced afterevaporation was crystallised from Et₂ O/petroleum ether to give thetitle compound (0.36 g), mp=123°-124° C.; ¹ H NMR (360MHz, D₆ --DMSO,300K) δ 9.02 (1H, d, J=7Hz), 7.90-7.87 (5H, m), 7.47-7.36 (3H, m), 4.86-4.79 (1H, m), 3.98-3.79 (2H, m), 3.43-3.38 (1H, m), 3.12-2.97 (5H, m),2.75 (3H, s), 2.64 (3H, s).

EXAMPLE 105-(3,5-Bistrifluoromethylphenyl)-2-t-butyloxycarbonylamino-1-(3-indolyl)-3-pentanone(a) N-Methoxy-N-methyl2-t-butyloxycarbonylamino-3-(3-indolyl)propionamide

N-@-BOC-L-tryptophan (100 g) was dissolved in dimethyl formamide (800ml) and triethylamine (101 g) was added. The reaction was cooled to -30°C. and isobutyl chloroformate (42.5 ml) was added, maintaining theinternal temperature to below -20° C. The reaction was stirred for 15minutes before adding N,O-dimethyl hydroxylamine hydrochloride (64 g)and then diluting the reaction with dichloromethane (1 l), maintainingthe internal temperature below 0° C. The reaction was stirred for 15minutes, poured into ethyl acetate (3 l) and washed with 10% citric acid(1 l), water (3×1 l), saturated sodium bicarbonate (1 l) and water (1l). The organic phase was dried (MgSO₄), filtered, and evaporated untilcrystallisation ensued. The suspension was diluted with petroleum ether,filtered and dried to yield the title compound (90.4 g); mp=129°-130°C.; ¹ H NMR (360MHz, D₆ DMSO) δ 10.80 (1H, s); 7.51 (1H, d, J=7Hz); 7.33(1H, d, J=7Hz); 7.16 (1H, s); 7.08-6.97 (3H, m); 4.62-4.58 (1H, m); 3.72(3H, s); 3.34 (3H, s); 3.02-2.81 (2H, m); 1.31 (9H, s).

b)2-t-Butyloxycarbonylamino-1-(3-indolyl)-4-dimethylphosphono-3-butanone

Dimethyl methane phosphonate (205 g) was dissolved in tetrahydrofuran(800 ml), cooled to -70° C.; and then treated with n-butyllithium (1.6Min hexane, 900 ml), maintaining the internal temperature of the reactionat below -55° C. The reaction was stirred for one hour before adding theproduct of part (a) (90 g). The reaction was stirred at -70° C. for 30minutes before quenching with saturated ammonium chloride. The resultingmixture was extracted with ethyl acetate and the organic extract waswashed with water (5×500 ml), dried (MgSO₄) and evaporated. The residuewas purified on silica (eluting with ethyl acetate) to yield the titlecompound as an oil (69.0 g); ¹ H NMR (360MHz, CDCl₃) δ 10.84 (1H, s),7.56 (1H, d, J=7Hz), 7.33 (1H, d, J=7Hz), 6.98 (1H, t, J=7Hz), 4.34-4.31(1H, m), 3.63 (6H, d, J=11Hz), 3.39 (2H, d, J=22Hz), 3.19-3.11 (1H, m),2.91-2.84 (1H, m); found: C, 55.73, H, 6.34; N, 6.80; C₁₉ H₂₇ N₂ O₆ Prequires C, 55.60; H, 6.63; N, 6.82%.

c)5-(3,5-Bistrifluoromethylphenyl)-2-t-butyloxycarbonylamino-1-(3-indolyl)-4-penten-3-one

Lithium chloride (14.13 g) was dried under vacuum (1 mm, Hg). A solutionof the product of part (b) (69.0 g) in acetonitrile (600 ml) was stirredwith diisopropylethylamine (43.3 g), and anhydrous lithium chloride(14.13 g) for 30 minutes before adding3,5-bistrifluoromethylbenzaldehyde (55 g) in acetonitrile (200 ml). Thereaction was stirred for two hours then the solvent was removed and theresidue partitioned between ethyl acetate and water. The organic phasewas washed with 10% citric acid (500 ml), water (500 ml), saturatedsodium bicarbonate (500 ml) and water (500 ml). The solution was dried(MgSO₄), filtered and evaporated. The residue was purified by columnchromatography on silica using ethyl acetate/petroleum ether (1:4) toyield the title compound as a pale yellow solid (77.6 g), mp=137°-138°C.; found: C, 59.23; H, 4.79; N, 5.35; C₂₆ H₂₄ F₆ N₂ O₃ requires C,59.32; H, 4.60; N 5.32%.

d)5-(3,5-Bistrifluoromethylphenyl)-2-t-butyloxycarbonylamino-1-(3-indolyl)-3-pentanone

The product of part (c) was heated under reflux with tri-n-butyltinhydride (51.12 g) in toluene for 20 hours. The reaction was cooled andpurified by column chromatography on silica using ethylacetate/petroleum ether (1:4) to yield the title compound as a whitesolid (37.1 g), mp=138°-140° C.; found: C, 59.23; H,4.90; N, 5.28; C₂₆H₂₄ F₆ N₂ O₃ requires C, 59.09, H, 4.96; N, 5.30%.

EXAMPLE 112-Amino-5-(3,5-bistrifluoromethylphenyl)-1-(3-indolyl)-3-pentanoneHydrochloride

The compound of Example 10 was treated in a similar manner to Example9(d) to yield a white solid, mp=84°-86° C.; found: C, 54.40; H, 4.25; N,6.10; C₂₁ H₁₈ F₆ N₂ O.HCl requires C, 54.26; H, 4.12; N, 6.03%

EXAMPLE 12 ##STR7##5-(3,5-Bistrifluoromethylphenyl)-2-(N,N-dimethylglycinamido)-1-(3-indolyl)-3-pentanoneHydrochloride

Prepared from the compound of Example 11 in manner to Example 9(e) togive the title compound as a white solid, mp=194°-196° C.; found: C,54.11; H, 4.65; N, 7.51; C₂₅ H₂₄ F₆ N₃ O₂.HCl.0.25H₂ O requires C,54.26; H, 4.64; N, 7.59%.

EXAMPLE 132-Benzamido-5-(3,5-bistrifluoromethylphenyl)-1-(3-indolyl)-3-pentanone

The compound of Example 11 (0.55 g) was dissolved in pyridine (10 ml)and benzoyl chloride (0.17 g) was added. The reaction was stirred for 16hours and then partitioned between 10% citric acid (50 ml) and ethylacetate (100 ml). The organic phase was washed with water (100 ml) andsodium bicarbonate solution (100 ml), dried (MgSO₄) and evaporated toyield an oil which was purified by chromatography on silica usingpetroleum ether/ethyl acetate (1:3) to yield the title compound as awhite solid, mp=119°-122° C.; found: C, 63.28; H, 4.25; N, 5.14; C₂₈ H₂₂F₆ N₂ O₂ requires C, 63.16, H, 4.16; N, 5.26%.

EXAMPLE 142-Acetamido-1-(3-benzo[b]thienyl)-5-(3,5-bistrifluoromethylphenyl)-3-oximinopentane

The compound of Example 4 (0.5 g) was dissolved in methanol followed byhydroxylamine hydrochloride (0.220 g) and sodium acetate (0.7 g). Thereaction was stirred for 16 hours, the solvent was removed and theresidue was dissolved in ethyl acetate (100 ml), washed with water (100ml), dried (MgSO₄), filtered and evaporated to yield an oil which waspurified by chromatography on silica using dichloromethane/Et₂ O (3:1)to yield the title compound isomer A as a white solid, mp=200°-201° C.;found: C, 54.79; H, 4.24; N, 5.19; C₂₃ H₂₀ F₆ N₂ O₂ S requires C, 54.98;H, 4.01; N, 5.58%. Further elution yielded the title compound isomer Bas a white solid, mp=200°-203° C.; found: C, 55.13; H, 4.14; N, 5.45;C₂₃ H₂₀ F₆ N₂ O₂ S requires C, 54.98; H, 4.01; N, 5.58 %.

EXAMPLE 152-Acetamido-5-(3,5-bistrifluoromethylphenyl)-1-(3,4-dichlorophenyl)-3-pentanone a) Diethyl (3,4-Dichlorobenzyl)acetamidomalonate

Diethyl acetamidomalonate (48.2 g) was dissolved in ethanol (250 ml)containing sodium ethoxide (10.2 g) and stirred at room temperature for0.5 hours before adding 3,4-dichlorobenzyl bromide and heating at refluxfor 3.5 hours. After cooling, the title compound was collected byfiltration and dried under reduced pressure(36.73 g).

b) Ethyl 2-Acetamido-3-(3,4-dichlorophenyl)propionate

The product of part (a) (5 g) was dissolved in ethanol and treated withsodium hydroxide (2N, 6.65 ml). The reaction mixture was stirred for onehour, neutralised with hydrochloric acid and the resulting precipitatewas filtered off and dissolved in 1,4 dioxan (50 ml) and heated underreflux for 3 hours. The solvent was evaporated and the residue wasdissolved in ethyl acetate (500 ml) and washed with sodium bicarbonate(100 ml) and water (100 ml), dried (MgSO₄), filtered and evaporated toyield the title compound (3.0 g).

c)2-Acetamido-5-(3,5-bistrifluoromethylphenyl)-1-(3,4-dichlorophenyl)-3-pentanone

The product of part (b) was treated in the same manner as Examples 1 and4 to yield the title compound as a white solid, mp=124°-126° C.; found:C, 50.35; H, 3.53; N, 2.69; C₂₁ H₁₇ Cl₂ F₆ NO₂ requires C, 50.42; H,3.42, N, 2.80%.

EXAMPLE 16 ##STR8##5-(3,5-Bistrifluoromethylphenyl)-2-(3-N,N-dimethylaminopropionamide)-1-(3-indolyl)-3-pentanoneHydrochloride

Prepared by the method of Example 12 using 3-N,N-dimethylaminopropionicacid and obtained as a white solid, mp 77°-80° C.; found: C, 55.53; H,5.26; N, 6.94. C₂₆ H₃₀ ClF₆ N₃ O₃ requires C, 53.66; H, 5.20; N, 7.22%.

EXAMPLE 175-(3,5-Bistrifluoromethylphenyl)-2-(4-(N,N-dimethylamino)butyramido)-1-(3-indolyl)-3-pentanoneHydrochloride

Prepared from the compound of Example 11 in a similar manner to Example9(e) using 4-(N,N-dimethylaminobutyric acid to give the title compoundas a white solid, mp 48°-51° C.; Found: C, 54.57; H, 5.38; N, 7.23. C₂₇H₂₉ F₆ N₃ O₂.HCl.H₂ O requires C, 54.41; H, 5.41; N, 7.05%.

EXAMPLE 185-(3,5-Bistrifluoromethylphenyl)-2-(5-(N,N-dimethylamino)pentanamido)-1-(3-indolyl)-3-pentanone

A solution containing the compound of Example 11 (1.1 g) indichloromethane (50 ml) was treated with chlorovaleryl chloride (0.52ml) and triethylamine (0.64 ml) for 16 hours. The reaction was dilutedwith dichloromethane, washed with dilute hydrochloric acid and aqueoussodium bicarbonate, dried (Na₂ SO₄) and concentrated to give an oil. Toa solution containing the forgoing oil in ethanol (5 ml) was addeddimethylamine (5 ml of a 33% solution in ethanol) and potassium iodide(50 mg). After stirring for 4 days the mixture was partitioned betweenethyl acetate and water. The ethyl acetate solution was separated, driedand concentrated and the residue purified by chromatography on silicagel eluting with ethyl acetate-methanol (95:5) to give the titlecompound, mp 140° C.; found: C, 59.31; H, 5.47; N, 7.37. C₂₈ H₃₁ F₆ N₃O.0.5H₂ O requires: C, 59.57; H, 5.71; N, 7.44.

EXAMPLE 195-(3,5-Bistrifluoromethylphenyl)-2-(cyclopropylcarboxamido)-1-(3-indolyl)-3-pentanone

To a solution of 4-bromobutyryl chloride (0.4 g) and triethylamine (0.61ml) in dichloromethane (20 ml) was added the compound of Example 11 (1.0g). After stirring for 16 hours the solution was washed with water,dried (Na₂ SO₄) and concentrated. Chromatography on silica gel elutingwith ethyl acetate/petroleum ether followed by crystallisation fromdiethyl ether/petroleum ether gave the title compound, mp 142°-145° C.:found: C, 60.66; H, 4.46; N, 5.59. C₂₅ H₂₂ F₆ N₂ O₂ requires C, 60.48;H, 4.47; N, 5.64.

EXAMPLE 205-(3,5-Bistrifluoromethylphenyl)-2-(3-phenylbutyramido)-1-(3-indolyl)-3-pentanone

Prepared by the method of Example 20 using phenyl butyric acid andomitting the final lithium hydroxide hydrolysis. Mp 133°-137° C.; found:C, 64.76; H, 4.87; N, 4.72. C₃₁ H₂₈ F₆ N₂ O₂ requires C, 64.80; H, 4.91;N, 4.88.

The following examples illustrate pharmaceutical compositions accordingto the invention.

EXAMPLE 21A Tablets Containing 1-25 mg of Compound

    ______________________________________                                                         Amount mg                                                    ______________________________________                                        Compound of formula (I)                                                                        1.0        2.0    25.0                                       Microcrystalline cellulose                                                                     20.0       20.0   20.0                                       Modified food corn starch                                                                      20.0       20.0   20.0                                       Lactose          58.5       57.5   34.5                                       Magnesium Stearate                                                                             0.5        0.5    0.5                                        ______________________________________                                    

EXAMPLE 21B Tablets Containing 26-100 mg of Compound

    ______________________________________                                                        Amount mg                                                     ______________________________________                                        Compound of formula (I)                                                                        26.0      50.0    100.0                                      Microcrystalline cellulose                                                                     80.0      80.0    80.0                                       Modified food corn starch                                                                      80.0      80.0    80.0                                       Lactose          213.5     189.5   139.5                                      Magnesium Stearate                                                                             0.5       0.5     0.5                                        ______________________________________                                    

The compound of formula (I), cellulose, lactose and a portion of thecorn starch are mixed and granulated with 10% corn starch paste. Theresulting granulation is sieved, dried and blended with the remainder ofthe corn starch and the magnesium stearate. The resulting granulation isthen compressed into tablets containing 1.0 mg, 2.0 mg, 25.0 mg, 26.0mg, 50.0 mg and 100 mg of the active compound per tablet.

EXAMPLE 22 Parenteral Injection

    ______________________________________                                                             Amount mg                                                ______________________________________                                        Compound of formula (I)                                                                              1 to 100 mg                                            Citric Acid Monohydrate                                                                              0.75 mg                                                Sodium Phosphate       4.5 mg                                                 Sodium Chloride        9 mg                                                   Water for Injections   to 1 ml                                                ______________________________________                                    

The sodium phosphate, citric acid monohydrate and sodium chloride aredissolved in a portion of the water. The compound of formula (I) isdissolved or suspended in the solution and made up to volume.

EXAMPLE 23 Topical Formulation

    ______________________________________                                                             Amount mg                                                ______________________________________                                        Compound of formula (I)                                                                              1-10 g                                                 Emulsifying Wax        30 g                                                   Liquid paraffin        20 g                                                   White Soft Paraffin    to 100 g                                               ______________________________________                                    

The white soft paraffin is heated until molten. The liquid paraffin andemulsifying wax are incorporated and stirred until dissolved. Thecompound of formula (I) is added and stirring continued until dispersed.The mixture is then cooled until solid.

SUBSTANCE P ANTAGONISM ASSAY A. Receptor Expression in Monkey KidneyCell Line (COS)

To express the cloned human neurokinin-1-receptor (NK1R) transiently inCOS, the cDNA for the human NK1R was cloned into the expression vectorpCDM9 which was derived from pCDM8 (INVITROGEN) by inserting theampicillin resistance gene (nucleotide 1973 to 2964 from BLUESCRIPT SK+(trademark, STRATAGENE, La Jolla, Calif., USA)) into the Sac II site.Transfection of 20 ug of the plasmid DNA into 10 million COS cells wasachieved by electroporation in 800 μl of transfection buffer (135 mMNaCl, 1.2 mM CaCl₂, 1.2 mM MgCl₂, 2.4 mM K₂ HPO₄, 0.6 mM KH₂ PO₄, 10 mMglucose, 10 mM N-2-hydroxyethyl-piperazine-N'-2-ethane sulphonic acid(HEPES) pH 7.4) at 260 V and 950 μF using the IBI GENEZAPPER (trademarkIBI, New Haven, Conn., USA). The cells were incubated in 10% fetal calfserum, 2 mM glutamine, 100 U/ml penicillin-streptomycin, and 90% DMEMmedia (GIBCO, Grand Island, N.Y., USA) in 5% CO₂ at 37° C. for threedays before the binding assay.

B. Stable Expression in Chinese Hamster Ovarian Cell Line (CHO)

To establish a stable cell line expressing cloned human NK1R, the cDNAwas subcloned into the vector pRcCMV (INVITROGEN). Transfection of 20 μgof the plasmid DNA into CHO cells was achieved by electroporation in 800μl of transfection buffer supplemented with 0.625 mg/ml Herring spermDNA at 300 V and 950 μF using the IBI GENEZAPPER (IBI). The transfectedcells were incubated in CHO media [10% fetal calf serum, 100 U/mlpenicillin-streptomycin, 2 mM glutamine, 1/500 hypoxanthine-thymidine(ATCC), 90% IMDM media (JRH BIOSCIENCES, Lenexa, Kans., USA), 0.7 mg/mlG418 (GIBCO)] in 5% CO₂ at 37° C. until colonies were visible. Eachcolony was separated and propagated. The cell clone with the highestnumber of human NK1R was selected for subsequent applications such asdrug screening.

C. Assay Protocol using COS or CHO

The binding assay of human NK1R expressed in either COS or CHO cells isbased on the use of ¹²⁵ I-substance P (¹²⁵ I-SP from DU PONT, Boston,Mass.) as a radioactively labeled ligand which competes with unlabeledsubstance P or any other ligand for binding to the human NK1R. Monolayercell cultures of COS or CHO were dissociated by the non-enzymaticsolution (SPECIALTY MEDIA, Lavellette, N.J.) and resuspended inappropriate volume of the binding buffer (50 mM Tris pH 7.5, 5 mM MnCl₂,150 mM NaCl, 0.04 mg/ml bacitracin, 0.004 mg/ml leupeptin, 0.2 mg/mlBSA, 0.01 mM phosphoramidon) such that 200 μl of the cell suspensionwould give rise to about 10,000 cpm of specific ¹²⁵ I-SP binding(approximately 50,000 to 200,000 cells). In the binding assay, 200 μl ofcells were added to a tube containing 20 μl of 1.5 to 2.5 nM of ¹²⁵ I-SPand 20 μl of unlabeled substance P or any other test compound. The tubeswere incubated at 4° C. or at room temperature for 1 hour with gentleshaking. The bound radioactivity was separated from unboundradioactivity by GF/C filter (BRANDEL, Gaithersburg, Md.) which waspre-wetted with 0.1% polyethylenimine. The filter was washed with 3 mlof wash buffer (50 mM Tris pH 7.5, 5 mM MnCl₂, 150 mM NaCl) three timesand its radioactivity was determined by gamma counter.

The activation of phospholiphase C by NK1R may also be measured in CHOcells expressing the human NK1R by determining the accumulation ofinositol monophosphate which is a degradation product of IP₃. CHO cellsare seeded in 12-well plate at 250,000 cells per well. After incubatingin CHO media for 4 days, cells are loaded with 5 μCi of ³ H-myoinositolin 1 ml of media per well by overnight incubation. The extracellularradioactivity is removed by washing with phosphate buffered saline. LiClis added to the well at final concentration of 10 mM with or without thetest compound, and incubation is continued at 37° C. for 15 min.Substance P is added to the well at final concentration of 0.3 nM toactivate the human NK1R. After 30 min of incubation at 37° C., themedium is removed and 0.1N HCl is added. Each well is sonicated at 4° C.and extracted with CHCl₃ /methanol (1:1 ). The aqueous phase is appliedto a 1 ml Dowex AG 1X8 ion exchange column. The column is washed with0.1N formic acid followed by 0.025M ammonium formate-0.1N formic acid.The inositol monophosphate is eluted with 0.2M ammonium formate-0.1Nformic acid and quantitated by beta counter.

The data in Table 1 were obtained for compounds of formula (I):

                  TABLE 1                                                         ______________________________________                                        SUBSTANCE P ANTAGONISM RESULTS                                                Compound of Ex #                                                                              IC.sub.50 @ NKIR (nM)                                         ______________________________________                                         1              350                                                            2 (Isomer A)   700                                                            2 (Isomer B)   300                                                            3 (Isomer A)   >1 μM                                                       3 (Isomer B)   350                                                            4              20                                                             5 (Isomer A)   190                                                            5 (Isomer B)   500                                                            6 (Isomer A)   500                                                            6 (Isomer B)   30                                                             7              200                                                            8              3                                                              9              30                                                            10              40                                                            11              15                                                            12              10                                                            13              14                                                            14 (Isomer A)   200                                                           14 (Isomer B)   300                                                           15              40                                                            16              2                                                             17              0.4                                                           18              0.6                                                           19              2                                                             20              2                                                             ______________________________________                                    

We claim:
 1. A compound of formula (I): ##STR9## wherein Q¹ is; aheterocyclic group selected from unsubstituted or substituted indolyl,benzothiophenyl and benzofuranyl, said substituents selected from C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, halo, cyano, nitro, trifluoromethyl,trimethylsilyl, SR^(a), SOR^(a), SO₂ R^(a), OR^(a), NR^(a) R^(b), NR^(a)COR^(b), NR^(a) COOR^(b), COOR^(a) or CONR^(a) R^(b), where R^(a) andR^(b) are defined below:the dotted line represents an optional covalentbond; one of X and Y represents H and the other of X and Y representshydroxy or C₁₋₆ alkoxy, or X and Y together form a group ═O or ═NOR⁵where R⁵ is selected from H and C₁₋₆ alkyl; R¹ and R² are eachindependently selected from H; C₁₋₆ alkyl optionally substituted byhydroxy, cyano, COR^(c), CO₂ R^(c), CONR^(c) R^(d), or NR^(c) R^(d)(where R^(c) and R^(d) are each independently selected from H, C₁₋₆alkyl and phenyl (C₀₋₄ alkyl) optionally substituted in the phenyl ringby one or more of C₁₋₆ alkyl, C₁₋₆ alkoxy, halo and trifluoromethyl);phenyl (C₁₋₄ alkyl) (optionally substituted in the phenyl ring by one ormore of C₁₋₆ alkyl, C₁₋₆ alkoxy, halo and trifluoromethyl); COR^(c) ;CO₂ R^(c) ; CONR^(c) R^(d) ; COC₁₋₆ alkylNR^(c) R^(d) ; CONR^(c)COOR^(d) ; and SO₂ R^(c) ; where R^(c) and R^(d) are as above defined;R³ is selected from H, C₁₋₆ alkyl and C₂₋₆ alkenyl; and R⁴ is phenyloptionally substituted by 1, 2, or 3 groups selected from C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, halo, cyano, nitro, trifluoromethyl,trimethylsilyl, OR^(a), SR^(a), SOR^(a), NR^(a) R^(b), NR^(a) COR^(b),NR^(a) CO₂ R^(b), CO₂ R^(a) and CONR^(a) R^(b), where R^(a) and R^(b)are independently selected from H, C₁₋₆ alkyl, phenyl andtrifluoromethyl; or a pharmaceutically acceptable salt thereof.
 2. Acompound as claimed in claim 1 wherein R³ is selected from H and C₁₋₆alkyl.
 3. A compound as claimed in claim 1 wherein R¹ and R² areselected from H, COR^(c) and COC₁₋₆ alkylNR^(c) R^(d).
 4. A compound asclaimed in claim 1 wherein the optional covalent bond is absent.
 5. Acompound as claimed in claim 1 wherein X and Y together represent ═O. 6.A compound as claimed in claim 1 wherein R⁴ is 3,5-disubstituted phenyl.7. A compound as claimed in claim 1 wherein Q¹ is 3-indolyl.
 8. Acompound as claimed in claim 1 selectedfrom:2-acetamido-1-(3-benzo[b]thienyl)-5-(3,5-bistrifluoromethylphenyl)-4-penten-3-one;2-acetamido-1-(3-benzo[b]thienyl)-5-(3,5-bistrifluoromethylphenyl)-4-penten-3-ol;2-acetamido-1-(3-benzo[b]thienyl)-5-(3,5-bistrifluoromethylphenyl)-3-methoxy-4-pentene;2-acetamido-1-(3-benzo[b]thienyl)-5-(3,5-bistrifluoromethylphenyl)-3-pentanone;2-acetamido-1-(3-benzo[b]thienyl)-5-(3,5-bistrifluoromethylphenyl)-3-pentanol;2-acetamido-1-(3-benzo[b]thienyl)-5-(3,5-bistrifluoromethylphenyl)-3-methoxypentane;2-acetamido-5-(3,5-bistrifluoromethylphenyl)-1-(3-indolyl)-4-penten-3-one;2-acetamido-5-(3,5-bistrifluoromethylphenyl)-1-(3-indolyl)-3-pentanone;1-(3-benzo[b]thienyl)-5-(3,5-bistrifluoromethylphenyl)-2-(N,N-dimethylglycinamido)-3-pentanone;5-(3,5-bistrifluoromethylphenyl)-2-t-butyloxycarbonylamino-1-(3-indolyl)-3-pentanone;2-amino-5-(3,5-bistrifluoromethylphenyl)-1-(3-indolyl)-3-pentanone;5-(3,5-bistrifluoromethylphenyl)-2-(N,N-dimethylglycinamido)-1-(3-indolyl)-3-pentanone;2-benzamido-5-(3,5-bistrifluoromethylphenyl)-1-(3-indolyl)-3-pentanone;2-acetamido-1-(3-benzo[b]thienyl)-5-(3,5-bistrifluoromethylphenyl)-3-oximinopentane;5-(3,5-bistrifluoromethylphenyl)-2-(3-N,N-dimethylaminopropionamido)-1-(3-indolyl)-3-pentanone;5-(3,5-bistrifluoromethylphenyl)-2-(4-(N,N-dimethylaminobutyramido)-1-(3-indolyl)-3-pentanone;5-(3,5-bistrifluoromethylphenyl)-2-(5-(N,N-dimethylamino)pentanamido)-1-(3-indolyl)-3-pentanone;5-(3,5-bistrifluoromethylphenyl)-2-(cyclopropylcarboxamido)-1-(3-indolyl)-3-pentanone;5-(3,5-bistrifluoromethylphenyl)-2-(3-phenylbutyramido)-1-(3-indolyl)-3-pentanone;andpharmaceutically acceptable salts thereof.
 9. A pharmaceuticalcomposition comprising a compound as claimed in claim 1 in associationwith a pharmaceutically acceptable carrier.
 10. A method for thetreatment of a physiological disorder associated with an excess oftachykinins, which method comprises administration to a patient in needthereof of a tachykinin-reducing amount of a compound according toclaim
 1. 11. A method according to claim 10 for the treatment of pain orinflammation.
 12. A method according to claim 10 for the treatment ofmigraine.
 13. A method according to claim 10 for the treatment ofarthritis.